title: Caudal fourth ventricular administration of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside regulates glucose and counterregulatory hormone profiles, dorsal vagal complex metabolosensory neuron function, and hypothalamic Fos expression.
abstract: This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, counterregulatory hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, Louisiana, USA.
authors.forename: Baher A
authors.initials: BA
authors.lastname: Ibrahim
authors.forename: Pratistha
authors.initials: P
authors.lastname: Tamrakar
authors.forename: Amit D
authors.initials: AD
authors.lastname: Gujar
authors.forename: Ajeesh Koshy
authors.initials: AK
authors.lastname: Cherian
authors.forename: Karen P
authors.initials: KP
authors.lastname: Briski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000818:Animals; D001016:Aortic Bodies / Q000166:cytology*; D001786:Blood Glucose / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D020546:Fourth Ventricle / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism; D061346:Laser Capture Microdissection; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D012263:Ribonucleosides; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D009419:Nerve Tissue Proteins; D016761:Oncogene Proteins v-fos; D043683:Receptors, Adenosine A2; D012263:Ribonucleosides; C074283:estradiol 3-benzoate; D000620:Aminoimidazole Carboxamide; D004958:Estradiol; C011651:acadesine; D055372:AMP-Activated Protein Kinases
keywords: A2 noradrenergic neurons; AICAR; Fos immunoreactivity; GLUT-3; GLUT-4; MCT-2; arcuate hypothalamic nucleus; corticosterone; glucagon; ovariectomy; paraventricular hypothalamic nucleus; subcutaneous estradiol capsule